Tumor biomarker analyses from the phase III ZODIAC study of docetaxel (D) plus or minus vandetanib (VAN) in second-line advanced NSCLC.

Abstract

7516 Background: VAN is a once-daily oral inhibitor of VEGFR, EGFR, and RET signaling. VAN (100 mg/day) + D significantly prolonged PFS in ZODIAC, which included prospective exploratory analyses of potential relationships between clinical outcome and tumor biomarkers. Methods: Pts (n=1,391) with stage IIIB/IV NSCLC (mean age, 58 yrs; 30% female; any histology) were randomized to VAN + D or D + placebo (P). Prespecified analyses were performed on archival tumor samples (n=570) from consenting pts (n=958): EGFR protein expression by immunohistochemistry (IHC, n=362), EGFR gene copy number by fluorescent in situ hybridization (FISH, n=348), and EGFR (n=347) and KRAS (n=330) gene mutation status (wild-type [WT] or mutation [MT]) by the ARMS assay. Results: Baseline characteristics of pts with evaluable tumor samples were generally consistent with all pts. High EGFR protein expression (≥1% tumor cells stained, IHC+) was detected in 318 (88%) evaluable samples, 123 (35%) samples were FISH+ (defined as high EGFR gene polysomy or EGFR gene amplification), 50 (14%) samples had EGFR MT (exons 18–21), and 43 (13%) samples had KRAS MT (exons 12–13). Consistent trends toward improved PFS, overall survival and objective response rate for pts with EGFR FISH+ or EGFR MT tumors were seen with VAN + D vs D + P (Table). No consistent trends for differential benefits were associated with EGFR protein expression or KRAS mutation status. Conclusions: Exploratory analyses suggest that EGFR gene copy number (FISH+) and EGFR mutation status (EGFR MT) may have some predictive value in identifying pts who receive most benefit from VAN + D in second-line NSCLC. n PFS OS ORR HR, 97.58% CI HR, 97.52% CI HR, 97.5% CI All 1,391 0.79, 0.70–0.90 0.91, 0.78–1.07 1.84, 1.29–2.64 EGFR IHC+ 318 0.80, 0.61–1.04 0.77, 0.55–1.07 1.68, 0.84–3.39 IHC- 44 0.82, 0.38–1.79 1.08, 0.45–2.62 2.17, 0.30–15.85 FISH+ 123 0.61, 0.39–0.94 0.48, 0.28–0.84 3.90, 1.02–14.82 FISH- 225 1.20, 0.87–1.65 1.13, 0.78–1.64 1.20, 0.46–3.10 MT 50 0.51, 0.25–1.06 0.46, 0.14–1.57 3.34, 0.80–13.89 WT 297 0.99, 0.76–1.31 0.93, 0.67–1.28 0.98, 0.41–2.33 KRAS MT 43 1.04, 0.51–2.15 0.78, 0.35–1.75 1.81, 0.11–30.83 WT 287 0.75, 0.57–1.00 0.87, 0.61–1.22 1.88, 0.89–3.97 Author Disclosure Employment or Leadership Position Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration AstraZeneca AstraZeneca AstraZeneca AstraZeneca Genzyme